Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS). GABA is produced by the conversion of glutamic acid to GABA by glutamic acid decarboxylase and is released by GABAergic neurons in the CNS. (Wong et al., 2003). Upon release, GABA binds to neuronal transmembrane GABA receptors. The GABAA receptor is a chloride ion channel which is regulated by GABA binding and is the major site for the inhibitory activities of GABA. Specifically, the binding of GABA to the GABAA receptor opens the chloride ion channel. In mature neurons, the opening of the chloride channel results in a decrease of the transmembrane potential and thereby inhibits neuronal excitation. (Olsen, 2002). Through this mechanism, GABA is known to regulate the activity of central noradrenergic, serotonergic, dopaminergic and acetylcholinergic neurons. (Wenk et al., 1991). As described below, GABAergic dysfunction has been linked to several disorders.
Schizophrenia is a mental disorder characterized by a loss of contact with reality, hallucinations, delusions, abnormal thinking, flattened affect, diminished motivation, and disturbed work and social functioning. (Merck Manual, Seventh Ed.). It has been hypothesized that decreased GABAergic transmission causes rearrangement, and possibly enlargement of sensory, memory and ‘cognitive’ fields, which may lead to overinclusive and disorganized thought processes associated with schizophrenia. Post-mortem studies of schizophrenic subjects have shown that defects of GABAergic neurotransmission are implicated in schizophrenia and bipolar disorder. (Bernes & Berretta, 2001).
Due to the inhibitory function of GABA in the CNS, disruptions in GABAeric function has been implicated in epilepsy (seizures), spasticity, stiff-person syndrome (SPS), premenstrual dysphoric disorder, drug addiction, anxiety disorders, and schizophrenia (Wong et al., 2003), and fertility disorders (Sullivan & Moenter, 2003).
Deficits in GABAA receptors have been linked to anxiety, epilepsy, and insomnia. (Möhler, 2006).
GABA levels were found to be lower in the cerebrospinal fluid of patients with spinocerebellar degeneration, neuro-Behçet's syndrome and Parkinson's disease. (Kuroda et al., 1982).
A loss of CB1 receptor control of GABA-mediated synaptic currents has been shown in the mouse model of attention-deficit/hyperactivity disorder. Specifically, in the mouse model of ADHD obtained by triple point mutation in the dopamine transporter (DAT) gene, sensitivity of CB1 receptors controlling GABA-mediated synaptic currents in the striatum was completely lost. (Castelli et al., 2011).